Notice that the title says ‘Causes’. There’s little doubt that “chronic fatigue syndrome” can be produced in a variety of ways. The definition is too broad and the responses to treatments are too variable for this disease not to have several, perhaps even numerous, causes.

complex system

Multiple theories abound regarding the cause of chronic fatigue syndrome. A heterogeneous population suggests several could be correct.

That said, some common findings have emerged; most ME/CFS researchers appear to believe ME/CFS is a multi-systemic disorder involving the autonomic, immune and neuroendocrine systems.

Triggering Chronic Fatigue Syndrome (ME/CFS): Infection, injury, physical or psychological stress, toxin exposure, vaccination and other stressful events have been reported to trigger ME/CFS.

Study findings suggesting that high cytokine levels and severe symptoms predispose people with colds to come down with ME/CFS are the closest, however, researchers have come to disentangling this complex process.

The Central Nervous System: Abnormal patterns of brain activity, reduced brain blood flows and brain volume, small brain lesions,high brain lactate levels, and others suggest areas of the brain involved in the stress response, energy production, concentration, motivation, fatigue and pain are damaged in chronic fatigue syndrome (ME/CFS). Natelson’s research suggests ME/CFS patients without mood disorders have increased rates of central nervous system abnormalities. Areas of particular interest in the brain include the brainstem, the prefrontal cortex, insula, orbitofrontal cortex and anterior cingulate, and the connections between these regions. Recent studies suggest neuroinflammation could be a core problem.

Immune Defects: The flu-like symptoms chronic fatigue syndrome (ME/CFS) patients often experience at the diseases onset has made the immune system an important research emphasis. Several immune abnormalities could contribute to the problems patients face. Many immune studies, however, have produced inconsistent findings.

  • Natural Killer (NK) and T-cell Dysfunction – NK dysfunction is consistently found and recent reports suggest a similar dysfunction may occurs in the T-cells.
  • Th1/Th2 Imbalance – There are two general branches (Th1/Th2) of the immune system. Some patients appear to have an over activation of the anti-inflammatory (Th2) branch and an under activation of the pro-inflammatory (Th1) branch of the immune system. This could cause increased rates of allergy and sensitivity on the one hand and difficulty fighting off pathogens on the other.
  • Th17 – recent studies suggest the Th17 system regulating inflammation and autoimmune processes may be affected.
  • Autoimmune – Two successful Rituximab trials have sparked interest in B-cells and autoimmune processes in ME/CFS.
  • Immune exhaustion – some studies suggest that immune exhaustion may be present in patients with longer duration illnesses. This immune exhaustion takes the form of reduced NK and T-cell activity and immune factor production. A similar process may be occurring in fibromyalgia.

An Undiagnosed Chronic Infection: Several researchers propose ‘atypical’ herpesvirus  (HHV6, EBV, Enterovirus) infections are triggering an immune response that is causing the symptoms of ME/CFS.  Others believe a difficult to diagnose brain infection (HHV6A) may be present.


With infectious onset being common, interest in pathogens is high. We should know much more about pathogens and ME/CFS by 2014.

Increased Sympathetic and Decreased Parasympathetic Nervous System (SNS/PNS) Activation: Narrowed blood vessels and low blood volume associated with increased SNS activity could caused reduced brain and muscle blood flows, heart abnormalities under stress and other problems seen in chronic fatigue syndrome (ME/CFS). Reduced PNS activity could also contribute to unrefreshing sleep.

Metabolic/Mitochondrial Issues – exercise studies are increasingly pointing to mitochondrial dysfunction as a possible culprit

Impaired Stress Response: Impaired hypothalamic-pituitary-adrenal (HPA) axis functioning (apparently at the hypothalamus) and reduced cortisol levels are present in some patients. Chronically impaired HPA axis functioning could set the stage for a Th2 imbalance but the  research into this area has tapered off in recent years.

Gut Flora Imbalance and Bacterial Translocation – Some studies and patient stories suggest that altered gut flora and weakened boundary junctions may be occurring in ME/CFS. Weakened gut boundary junctions that allow movement of gut materials into the blood could spark an immune response in some people with ME/CFS. Similar translocations could be occurring in the blood brain barrier.

abdomen-womanKynurenine Pathway Activation – activation of the kynurenine pathway commonly occurs in neurological and neuropsychiatric disorders. Inflammation sparks tryptophan to be metabolized via kynurenine pathway which produces free radicals and elements that excite the central nervous system.

Genetics: Recent studies suggest a strong genetic component is present in both ME/CFS and FM. Several gene mutation studies have found increased rates of neuro-endocrine and immune mutations. The Open Medicine Institute is currently examining HLA genes in ME/CFS.

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